Compounds containing a halogen element, i.e., those in Group 17 of the periodic table are commonly termed “halogens” or “halogen compounds.” These elements are iodine (I), fluorine (F), chlorine (Cl), bromine (Br) and astatine (At). The artificially created element 117 (ununseptium) may also be a halogen. The term “halogen” means “salt-former,” and compounds containing halogens are usually called “salts.” All halogens have 7 electrons in their outer shells, giving them an oxidation number of −1. The halogens all form binary compounds with hydrogen known as the hydrogen halides: hydrogen fluoride (HF), hydrogen chloride (HCl), hydrogen bromide (HBr), hydrogen iodide (HI), and hydrogen astatide (HAt). When in aqueous solution, the hydrogen halides are known as hydrohalic acids. The names of these acids are as follows: hydrofluoric acid, hydrochloric acid, hydrobromic acid, and hydroiodic acid. Chlorine plays a biological role in higher animal life as aqueous chloride anions, which are included in the electrolyte makeup of inter- and intra-cellular fluids. Iodine is known to be needed by our bodies in trace amounts, particularly by the thyroid gland, and iron deficiency can cause goiter. The other three halogens have no known biological role.
In medicine, ischemia-reperfusion injuries are commonly associated with blood loss or reduced blood flow to a tissue or organ. Ischemia-reperfusion injury is a complex phenomenon often encountered when blood flow is restricted to an organ or tissue due to injury or blood loss, and also in surgical practice. Ischemia generally refers to a restriction in blood supply to tissues, causing a shortage of oxygen and glucose needed for cellular metabolism. Ischemia is generally caused by problems with blood vessels, with resultant damage to or dysfunction of tissue. It also refers to local anemia in a tissue or organ, which may result from injury or congestion (e.g., vasoconstriction, thrombosis or embolism). The consequences of such injury are local and remote tissue destruction, and sometimes death. Reperfusion refers generally to the restoration of blood flow to an ischemic tissue or organ. Primary reperfusion therapies, including primary percutaneous coronary intervention (PCI) and thrombolysis, are the standard of care for the treatment of acute coronary syndromes. Prompt restoration of blood flow to ischemic myocardium limits infarct size and reduces mortality. Unfortunately, however, the return of blood flow can also result in tissue, e.g., cardiac, damage and complications, referred to as reperfusion injury. Reperfusion injury is the tissue damage caused when blood supply returns to the tissue after a period of ischemia or lack of oxygen. The absence of oxygen and nutrients from blood during the ischemic period creates a condition in which the restoration of circulation results in inflammation and oxidative damage through the induction of oxidative stress rather than restoration of normal function. For example, in myocardial ischemia, considerable evidence attributes reactive oxygen species (ROS), produced either by the myocardium itself or by infiltrating inflammatory cells, as an early event in this process. Once produced, ROS can lead to cellular damage through a number of pathways including direct damage to membranes and proteins or indirect damage through the activation of pro-apoptotic pathways.
Effective therapies to reduce or prevent ischemic and reperfusion injuries have proven elusive. Despite an improved understanding of the pathophysiology of these processes and encouraging preclinical trials of multiple agents, most of the clinical trials to prevent ischemia-reperfusion injury have been disappointing. Accordingly, therapies for treating or limiting injuries and damage resulting from hypoxia, ischemia and/or reperfusion remain an active area of investigation.
Clearly, there is a need in the art for new pharmaceutical compositions and methods for treating or preventing ischemic and/or reperfusion injuries, e.g., including those that may be conveniently administered to patients, both in a controlled medical environment e.g., for treatment of disease, as a treatment in the field during an emergency, or in critical care in response to a catastrophic injury or life-threatening medical event. The present invention meets this need by providing pharmaceutical compositions comprising active agents, which are demonstrated herein to protect animals from injury resulting from hypoxic and/or ischemic conditions, as well as other injuries and disease conditions.